The long term objective of this project is to design a strategy(s) to improve cardiac function in the aged population after myocardial infarction (Ml). The impaired angiogenic capability of the aged heart after Ml may be due to diminished angiogenesis (sprouting of preexisting vessels) and/or vasculogenesis (incorporation of progenitor cells in the newly formed vessels). In contrast to the known impaired angiogenesis, vasculogenesis which is mediated by circulating and/or resident tissue EPCs, is less characterized in the aged heart after Ml. Therefore, determining the role of EPCs in ischemia-induced neovascularization is the main focus of this application. This will provide the foundation to develop an EPC-based strategy to improve cardiac function after Ml in the aged. These EPCs may deliver the needed cytokines for vascularization. Three routes of cell delivery are utilized, intravenous injection, direct injection into the infarct, and delivery using a 3-D collagen scaffold grafted onto the myocardium after Ml. The scaffold approach serves as a model to study cardiac angiogenesis in vivo, and to locally deliver stem cells and/or angiogenic factors to the injured myocardium. Our data, using Brown Norway Fisher 344 cross (BNXF344) rats at different ages (6 weeks, 6 months, and 24 months), indicate that the scaffold initially stabilizes the infarct, promotes angiogenesis, and is replaced by viable tissue. Based on these results, and the current literature, our hypothesis is that cell transplantation of genetically-modified EPCs will enhance ischemia-induced vascularization and will lead to improved cardiac function in the aged after Ml. To test this hypothesis, BNXF344 rat model will be used to determine if the depressed ischemia-induced neovascularization in the aged can be improved using EPC; to elucidate the mechanisms of age-mediated diminished EPCs-contribution to this process; and to determine if overexpression of CXCR4 on EPCs enhances stem cell recruitment to the infarct leading to improve vasculogenesis/cardiac function. Our research will help fill specific gaps in our present knowledge regarding the greater susceptibility to loss of cardiac function after Ml in the elderly and methods to assist recovery. These gaps include: no established treatment exits for the diminished angiogenic capability of the aged heart after Ml; the specific contribution of progenitor cells in this process is unknown; and aging effects on EPCs function are unclear ? ? ?
